Abstract

At present, there is no cure or vaccine for the devastating new highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has affected people globally. Herein, we identified potent phytocompounds from two antiviral plants Momordica charantia L. and Azadirachta indica used locally for the treatment of viral and parasitic infections. Structure-based virtual screening and molecular dynamics (MD) simulation have been employed to study their inhibitory potential against the main protease (M^pro) SARS-CoV-2. A total of 86 compounds from M. charantia L. and A. indica were identified. The top six phytocompounds; momordicine, deacetylnimninene, margolonone, momordiciode F2, nimbandiol, 17-hydroxyazadiradione were examined and when compared with three FDA reference drugs (remdesivir, hydroxychloroquine and ribavirin). The top six ranked compounds and FDA drugs were then subjected to MD simulation and pharmacokinetic studies. These phytocompounds showed strong and stable interactions with the active site amino acid residues of SARS-CoV-2 Mpro similar to the reference compound. Results obtained from this study showed that momordicine and momordiciode F2 exhibited good inhibition potential (best MMGBA-binding energies; −41.1 and −43.4 kcal/mol) against the M^pro of SARS-CoV-2 when compared with FDA reference anti-viral drugs (Ribavirin, remdesivir and hydroxychloroquine). Per-residue analysis, root mean square deviation and solvent-accessible surface area revealed that compounds interacted with key amino acid residues at the active site of the enzyme and showed good system stability. The results obtained in this study show that these phytocompounds could emerge as promising therapeutic inhibitors for the M^pro of SARS-CoV-2. However, urgent trials should be conducted to validate this outcome.

Communicated by Ramaswamy H. Sarma

摘要

目前，对于已影响全球人民的毁灭性新型高传染性严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2)，尚无治疗方法或疫苗。在此，我们从当地用于治疗病毒和寄生虫感染的两种抗病毒植物苦瓜和印楝中鉴定出有效的植物化合物。基于结构的虚拟筛选和分子动力学 (MD) 模拟已被用于研究它们对主要蛋白酶 (M ^pro ) SARS-CoV-2 的抑制潜力。苦瓜和籼稻共有 86 种化合物被识别。前六名的植物化合物；研究了苦瓜碱、脱乙酰亚胺、马戈洛酮、苦瓜酮 F2、宁班二醇、17-羟基氮杂二酮，并与三种 FDA 参考药物（瑞德西韦、羟氯喹和利巴韦林）进行了比较。然后对排名前六的化合物和 FDA 药物进行 MD 模拟和药代动力学研究。这些植物化合物与 SARS-CoV-2 Mpro 的活性位点氨基酸残基表现出强而稳定的相互作用，类似于参考化合物。从这项研究中获得的结果表明，苦瓜碱和苦瓜苷 F2 对 M ^{pro表现出良好的抑制潜力（最佳 MMGBA 结合能；-41.1 和 -43.4 kcal/mol）}SARS-CoV-2 与 FDA 参考抗病毒药物（利巴韦林、瑞德西韦和羟氯喹）相比。每残基分析、均方根偏差和溶剂可及表面积表明，化合物与酶活性位点的关键氨基酸残基相互作用，并显示出良好的系统稳定性。本研究获得的结果表明，这些植物化合物可能成为SARS-CoV-2 M ^{pro的有希望的治疗抑制剂。}然而，应进行紧急试验以验证这一结果。

由 Ramaswamy H. Sarma 传达